Plasmodium vivax transmitted from man to monkey to man.

Blood forms of human vivax malaria infected splenectomized night monkeys (Aotus trivirgatus). Anopheles albimanus mosquitoes transmitted the in fection from a monkey to two human volunteers; parasites and symptoms ap peared 11 days later. Blood forms of vivax malaria from each of the two humans infected other night monkeys.

Decreased expression of murine PPARgamma in adipose tissue during endotoxemia.

Infection-induced hyperlipidemia develops due to a combination of factors, one of which is decreased clearance of lipids from the bloodstream due to depressed synthesis of lipoprotein lipase (LPL). Recently, the peroxisome proliferator activated receptors (PPARs) have been shown to be important in the regulation of LPL, particularly PPARgamma. PPARgamma and its heterodimerization partner, RXR alpha have been shown to be transcriptional activators of LPL in co-transfection analysis. Therefore, we hypothesized that the decrease in LPL expression during endotoxemia may be a result of depressed PPARgamma expression. In these studies, we examined the effect of endotoxin or its proximal mediator, tumor necrosis factor (TNF), on the expression of PPARgamma in white (WAT) and brown adipose tissue (BAT) in CD-1 mice. We report that treatment with endotoxin, but not TNF, transiently decreased PPARgamma mRNA levels 4 hr after treatment. However, endotoxin or TNF treatment decreased PPARgamma protein levels after 18 hr, which was at a time when LPL mRNA levels were also depressed. These data suggest that decreased PPARgamma expression following endotoxin or TNF treatment may contribute to the hyperlipidemia due to decreased expression of LPL, which would impair triglyceride clearance.

Does surgical subspecialization in pediatrics provide high-quality, cost-effective patient care?

OBJECTIVE: To determine if pediatric surgical subspecialization provides cost-effective, high-quality pediatric patient care. METHODS: Ureteroneocystostomy inpatients over 4 years were studied. Hospital charges and complications were compared between general urologists and fellowship-trained pediatric urologists. RESULTS: Hospital charges were significantly less ($1095) for patients under the care of a pediatric urologist. Complication rates were also lower. CONCLUSIONS: Pediatric urology subspecialization offers high-quality, cost-effective pediatric patient care.

Determining the optimal dosage regimen for H2-receptor antagonist therapy--a dose validation approach.

A large number of clinical studies have been performed to establish the safety and efficacy of H2-receptor antagonist therapy. Few if any of these studies have attempted to address the rationale for the dosage and/or dosage regimens being studied. This study is the first large-scale clinical trial, the purpose of which is to validate the chosen regimen and to address the issue of an optimal therapy for a specific patient population. A regimen of a single nightly dosage is generally acknowledged to offer the potential for improved patient compliance. Furthermore, recent research had suggested that suppression of nocturnal acid secretion is all that is required to heal duodenal ulcers. Hence such a regimen offered the potential for an effective lowered dosage of cimetidine with minimal interference with gastric physiology, increased safety and substantial efficacy. This multicentre, double-blind, placebo-controlled trial therefore evaluated a 4-week course of single night-time dosage of cimetidine. After 4 weeks of treatment the cumulative, endoscopically proven, ulcer healing rate with an 800 mg regimen was 73%, which was statistically higher and significantly superior to the 41% healing seen with placebo (P less than 0.001). The 400 mg nocte dosage regimen of cimetidine normally used as maintenance therapy was significantly inferior to the 800 mg nocte regimen (P = 0.01), and increasing the dosage to 1600 mg nocte for 4 weeks failed to provide a significant improvement in healing over the 800 mg nocte regimen. This 800 mg nocte regimen provided rapid pain relief, with 75% of the patients being free of night-time pain and 65% free of day-time pain, by the end of the first week. The 400 mg 'maintenance dosage' was unable to provide this degree of rapid, complete and early relief to patients with a duodenal ulcer. Furthermore, increasing the dosage to 1600 mg nocte failed to increase the level of early pain relief significantly, perhaps because the extensive response of duodenal ulcer patients to the 800 mg nocte regimen leaves little room for improvement. Based both on the early symptom relief and the ulcer healing rate during 4 weeks of treatment, it is concluded that an 800 mg night-time dosage of cimetidine may be an optimal regimen for many duodenal ulcer patients, particularly those who in the physician's opinion will benefit from a once-daily regimen.

Acute treatment of benign gastric ulcer with once-daily bedtime dosing of cimetidine compared with placebo.

This multicentre, double-blind study evaluated the efficacy of cimetidine 800 mg nocte compared to placebo for ulcer healing and pain relief in patients with endoscopically confirmed, benign gastric ulcers treated for up to 8 weeks. Cimetidine accelerated ulcer healing throughout the study. More cimetidine-treated patients (35 of 82, 43%) than placebo-treated patients (26 of 79, 33%) had healed ulcers after 4 weeks of therapy. Similarly, after 6 and 8 weeks of treatment, cimetidine continued to have superior healing rates, 76% (59 of 78, P = 0.02) and 91% (69 of 76, P = 0.02) heal rates for cimetidine recipients compared with 58% (42 of 73) and 74% (52 of 70) for placebo. For every week of the study except the second, a greater proportion of cimetidine-treated patients were free of daytime and night-time pain than placebo-treated patients; the differences were statistically significant for night-time pain. Adverse reaction profiles were similar for the cimetidine and placebo groups. In conclusion, cimetidine 800 mg nocte was comparably safe and significantly more effective than placebo in accelerating healing and relieving pain in the treatment of acute, benign gastric ulcer.

Chemotherapy of Plasmodium vivax in Saimiri and Aotus models.

Three standard antimalarial compounds were tested against trophozoite or sporozoite induced infections of the Panamanian Achiote strain of Plasmodium vivax in two species of monkeys. In Saimiri sciureus (24 subjects) and Aotus trivirgatus (11 subjects), parasite clearance from the peripheral blood averaged 3 days after initiating chloroquine therapy (total dose of 25 mg base/kg body weight over 3 days or single dose of 10 mg base/kg. Trophozoite induced infections were cured in all of 10 Saimiri and all of 6 Aotus, as indicated by the absence of relapses. Relapses did occur in 3 of 11 tests with Saimiri and 3 of 5 tests with Aotus against sporozoite induced infections. Subpatent periods ranged from 38 to 111 days among intact and splenectomized hosts. This is the first chemotherapeutic evidence for the persistence of exoerythrocytic stages of P. vivax in New World monkeys. Pyrimethaminr (single dose of 1 mg/kg) cured trophozoite induced infections in all of five Saimiri hosts. Radical cure of sporozoite induced infections was accomplished in each of six trials with chloroquine (25 mg base/kg) plus primaquine (1 mg base/kg for 14 days). The primary attack or relapse was treated. These models warrant further investigation in chemotherapy.

Experimental infection of sheep with Naegleria fowleri of human origin.

A strain of Naegleria fowleri, isolated from a child who died of primary amebic meningoencephalitis in Florida, was instilled in the nostrils of a sheep to determine whether livestock are susceptible to infection with free-living amebae. The animal died 7 days later from amebic infection of the central nervous system. N. fowleri were recovered from the brain and spinal cord of the animal. A control, saline-instilled sheep that had been pair-caged with the infected animal remained healthy.

Globalization of the pharmaceutical industry: the physician's role in optimizing drug use.

In this new era of globalization, the physician must consider cultural differences in choosing methods of disseminating information so that practitioners in diverse settings may optimize drug usage. In addition, increasing competition, stimulated by the imminent unification of the European market in 1992, demands that the industry physician be concerned with developing possible new indications and cost-effective applications. These factors will enhance roles for the medical affairs physician in the pharmaceutical industry.

Molybdate-dependent expression of dimethylsulfoxide reductase in Rhodobacter capsulatus.

Expression of the dimethylsulfoxide respiratory (dor) operon of Rhodobacter is regulated by oxygen, light intensity and availability of substrate. Since dimethylsulfoxide reductase contains a pterin molybdenum cofactor, the role of molybdate in the regulation of dor operon expression was investigated. In this report we show that the molybdate-responsive transcriptional regulator, MopB, and molybdate are essential for maximal dimethylsulfoxide reductase activity and expression of a dorA::lacZ transcriptional fusion in Rhodobacter capsulatus. In contrast, mop genes are not required for the expression of the periplasmic nitrate reductase or xanthine dehydrogenase in R. capsulatus under conditions of molybdenum sufficiency. This is the first report demonstrating a clear functional difference between the ModE homologues MopB and MopA in this bacterium. The results suggest that MopA is primarily involved in the regulation of nitrogen fixation gene expression in response to molybdate while MopB has a role in nitrogen fixation and dimethylsulfoxide respiration.

An evaluation of cimetidine and ranitidine in the pain relief and acute healing of duodenal ulcer disease.

In a multicenter, single-blind, randomized trial, the effectiveness in pain relief and healing of three regimens of H2-receptor antagonists was compared in 338 patients with endoscopically confirmed active duodenal ulcers, 112 receiving cimetidine 300 mg four times daily (QID), 110 receiving cimetidine 800 mg at bedtime (HS), and 116 receiving ranitidine 300 mg HS. Evaluation of the immediate symptomatic response during the first 24 hours of therapy showed that a greater proportion of patients with nighttime pain were improved on HS regimen and a greater portion of patients with daytime pain were improved on QID regimen. With continued treatment the differences between a once-daily and a four-times-daily regimen disappeared and the HS regimen provided as much daytime pain relief as the QID regimen. For the two once-daily regimens where ranitidine and cimetidine were directly compared, a greater proportion of patients on cimetidine 800 mg HS had an immediate symptomatic improvement than on ranitidine 300 mg HS. When those who smoked were evaluated separately this difference was also evident. During the first 24 hours, a total of 68% of the smokers in the cimetidine HS treatment groups had improvement in daytime pain versus 44% of patients in the ranitidine group at day one. Nighttime pain relief in smokers on day one was apparent in 78% of the patients receiving the cimetidine HS regimen, in contrast to 67% of ranitidine-HS-treated patients. At the completion of a four-week course of treatment, both physicians' and patients' global assessments of the reduction in the severity and frequency of ulcer-related symptoms significantly favored cimetidine HS over ranitidine HS. These results after four weeks of treatment were corroborated by the endoscopy data, which showed 71% of patients in the cimetidine HS group were healed, compared with 63% in the ranitidine HS group. The 300 mg QID cimetidine regimen produced a 69% healing rate. For those patients whose ulcers were unhealed by the end of four weeks of treatment, a further course of treatment produced almost 9C% healing in all treatment groups and symptomatic relief in virtually all patients. None of the regimens was associated with unexpected adverse effects and all patients tolerated the treatments well. The results of this study confirm the efficacy and safety of single bedtime doses of cimetidine or ranitidine, as well as the four-times-daily cimetidine regimen, in the acute treatment of duodenal ulcers.(ABSTRACT TRUNCATED AT 400 WORDS)

Efficacy of once-daily cimetidine in preventing recurrence of duodenal ulcer.

In a prospective multicenter trial, 88 patients with acute duodenal ulcers that were healed with ranitidine were randomly assigned to receive maintenance treatment with either cimetidine 400 mg (n = 45) or placebo (n = 43) at bedtime for six months. Ten percent of the patients experienced moderate or severe pain both during the day and at night while on placebo during the maintenance phase. The average proportion of cimetidine patients experiencing moderate or severe pain during the day or night was 50% and 80% lower than placebo, respectively. Ulcer-like symptoms prompted endoscopy in 44% (19 of 43) of the placebo patients compared with 18% (eight of 45) of patients receiving cimetidine (P = 0.009). At the completion of the maintenance study, cumulative symptomatic ulcer recurrence rates were 28% (12 of 43) for those on placebo compared with 13% (six of 45) for cimetidine patients. The adverse drug effects noted were similar between treatment groups, with no unexpected reactions reported. A low dose of cimetidine (400 mg) at bedtime effectively reduced the incidence of gastrointestinal symptoms that were severe enough to prompt endoscopy as well as the actual recurrence of ulcers in those patients who had responded to initial therapy with ranitidine, but who continued to be at increased risk of reulceration.

The efficacy of cimetidine in the treatment of "resistant" duodenal ulcers.

In a prospective multicenter trial, 43 patients with acute duodenal ulcers unhealed after four weeks of treatment with an H2-receptor antagonist, ranitidine, were switched to treatment with another H2-receptor antagonist, cimetidine. Sixty-eight percent of the unhealed patients were successfully healed; of these patients, 81% were free of daytime pain and 89% were free of nighttime pain. Of those with residual pain, 71% and 50% showed improvement in daytime and nighttime pain severity, respectively. There were no unexpected adverse reactions reported or clinically significant changes in laboratory values measured during the study. It is concluded that cimetidine is highly effective both in healing duodenal ulcers unresponsive to ranitidine therapy and in providing continued relief of daytime and nighttime pain.

Antihypertensive effectiveness of very low doses of hydrochlorothiazide: results of the PHICOG Trial.

A large, multicenter, randomized, placebo-controlled, double-blind trial was carried out to determine the effects of the lowest dose of commercially available hydrochlorothiazide. Thus, Dyazide (which contains 25 mg of hydrochlorothiazide and 50 mg of triamterene in an approximately 50% bioavailable form), one capsule, was given daily to patients with either mild or moderate hypertension (supine diastolic blood pressure of 95 to 115 mmHg) for eight weeks. At the end of this eight-week period, supine diastolic blood pressure (SDBP) fell by 11.3 +/- 6.7 mmHg (mean +/- SD) in the Dyazide-treated compared to 4.6 +/- 6.9 mmHg in the placebo-treated group (P less than 0.001). In two thirds of the patients receiving active treatment the fall in SDBP was more than 10 mmHg, and in over half SDBP was completely normalized (ie, SDBP less than 90 mmHg). Supine systolic blood pressure fell by 14.7 +/- 12.3 mmHg in the Dyazide-treated group compared to 5.3 +/- 11.6 mmHg in the placebo-treated group (P less than 0.001). Approximately 80% of the antihypertensive effect occurred within two weeks and after four weeks there was no further significant reduction. Mildly (SDBP = 95 to 104 mmHg) and moderately (SDBP = 105 to 115 mmHg) hypertensive patients responded similarly to treatment. All studied subpopulations responded to treatment with a reduction of SDBP of at least an average of 10 mmHg; the best responders were blacks, women, the elderly (greater than 65 years old), and patients weighing less than 170 lbs. Side effects were mild and infrequent. In conclusion, by examining the effects of Dyazide (one capsule/day), this investigation demonstrated the effectiveness of low-dose hydrochlorothiazide in antihypertensive therapy and quantified it both in the general population and in clinically relevant subpopulations.

Clinical evaluation of clotrimazole. A broad-spectrum antifungal agent.

The efficacy and safety of the broad-spectrum, topically applied antifungal agent clotrimazole were evaluated in two double-blind, multicentric trials. Ten investigators reported on a total of 1,361 cases in which a 1% solution or a 1% cream formulation was compared with its respective vehicle. Clotrimazole was therapeutically effective, as confirmed by mycological cure (negative microscopy and culture) and clinical improvement, in tinea pedis, tinea cruris, tinea corporis, pityriasis versicolor, and cutaneous candidasis. Furthermore, species identification established the efficacy of clotrimazole against Trichophyton rubrum, T mentagrophytes, Epidermophyton floccosum, Microsporum canis, Malassezia furfur (Pityrosporum orbiculare), and Candida albicans. Safety was demonstrated by the low incidence of possibly drug-related adverse experiences, namely, 19 (2.7%) of 699 patients who were treated with clotrimazole, of whom four (0.6%) discontinued treatment.

Chemistry, pharmacology, antiarrhythmic efficacy and adverse effects of tocainide hydrochloride, an orally active structural analog of lidocaine.

Tocainide is an orally effective antiarrhythmic agent, structurally and pharmacologically similar to lidocaine. It appears to be free of marked negative hemodynamic or electrophysiologic effects in patients with heart disease, despite a high frequency of minor and often transient central nervous system and gastrointestinal side effects. Tocainide is effective in suppressing ventricular arrhythmias in a variety of settings. This agent may be a useful addition to our antiarrhythmic armamentarium.

Experimental transmission by mosquitoes of Plasmodium hermani between domestic turkeys and pen-reared bobwhites.

Plasmodium hermani was experimentally transmitted from domestic turkey poults (Meleagris gallopavo) to pen-reared bobwhites (Colinus virginianus) and then from these bobwhites back to domestic turkey poults. Transmission was achieved by Culex nigripalpus both by bites of the mosquito and by intraperitoneal injection of sporozoites. All of the 23 bobwhites and the 13 turkeys exposed to sporozoites became infected. These results indicate that the bobwhite might be a reservoir host for this malaria of wild turkeys in nature.

Experimental Naegleria fowleri meningoencephalitis in sheep: light and electron microscopic studies.

A sheep infected intranasally with Naegleria fowleri of human origin died 7 days after inoculation. The olfactory lobes were distinctly soft and friable. Histologic findings indicated suppurative leptomeningitis and hemorrhagic necrosis in the olfactory lobes. Protozoa were disseminated in the necrotic areas, particularly in perivascular locations; vasculitis was also observed. Meningitis and perivascular cuffing with lymphocytes were evident in the cerebrum, cerebellum, pons, medulla, and cervical spinal cord. Electron microscopy disclosed trophozoites only in the olfactory lobes. The amebae contained a central nucleus with a distinct, electron-dense nucleolus. The cytoplasm contained myelinated figures, lipid-like vacuoles, open vesicles, electron-dense granules, mitochondria, numerous free ribosomes, scant rough endoplasmic reticulum, and occasionally a phagocytized erythrocyte. Trophozoites were grouped close to arterioles, except when phagocytized by a neutrophil or endothelial cell.

Mosquito transmission of wild turkey malaria, Plasmodium hermani.

Culex nigripalpus experimentally transmitted Plasmodium hermani, a plasmodium of wild turkeys (Meleagris gallopavo) in Florida. The mosquitoes were infected by feeding upon blood induced parasitemias in domestic turkey poults. The resulting sporozoites, transmitted by either mosquito bites or injection, produced malaria infections in domestic poults.

Effect of ivermectin on murine mites.

Two SC injections of ivermectin (200 micrograms/kg of body weight), given one week apart, safely and effectively eliminated mite infestations (Myocoptes musculinus and Myobia musculi) from laboratory mice. When one 200 micrograms/kg or one 100 micrograms/kg injection of ivermectin was given to the mice, mite infestations were reduced temporarily.